Deletion of peroxiredoxin 6 potentiates lipopolysaccharide-induced acute lung injury in mice.

Abstract

OBJECTIVE:

To investigate the role and signaling pathway of peroxiredoxin 6, a newly identified peroxidase, in lipopolysaccharide-induced acute lung injury.

DESIGN:

Prospective, randomized, controlled study.

SETTING:

Research laboratory.

SUBJECTS:

Peroxiredoxin 6 (-/-) and wild-type C57BL/6 mice.

INTERVENTIONS:

Wild-type or peroxiredoxin 6 (-/-) mice were challenged by intratracheal instillation of lipopolysaccharide (5 mg/kg) for 4 hrs or 24 hrs for lung injury measurement. In other studies, peritoneal macrophages, isolated from wild-type and peroxiredoxin 6 (-/-) mice, were preincubated in presence or absence of mitogen-activated protein kinases inhibitors for 30 mins before being stimulated with lipopolysaccharide (1 μg/mL) for 4 hrs.

MEASUREMENTS AND MAIN RESULTS:

Bronchoalveolar lavage myeloperoxidase activity and the lung injury score were significantly increased in peroxiredoxin 6 (-/-) mice compared with wild-type mice after lipopolysaccharide instillation at both 4 hrs and 24 hrs. Hydrogen peroxide and malondialdehyde levels, as well as nuclear factor-κB activities, tumor necrosis factor-α, interleukin-1β, and matrix metalloproteinase-9 messenger RNA, protein concentration, and activities were significantly increased whereas total antioxidative capability was markedly decreased in lungs of peroxiredoxin 6 (-/-) mice compared with wild-type mice. In vitro studies showed intracellular reactive oxygen species levels and release of tumor necrosis factor-α, interleukin-1, and matrix metalloproteinase-9 were significantly increased in macrophages from peroxiredoxin 6 (-/-) mice compared with that from wild-type mice after lipopolysaccharide stimulation. Cytokines release was partially suppressed by extracellular signal-regulated kinase and c-Jun N-terminal kinase inhibitors, but not by the p38 mitogen-activated protein kinase inhibitor.

CONCLUSIONS:

Deletion of peroxiredoxin 6 exaggerates lipopolysaccharide-induced acute lung injury and inflammation with increased oxidative stress, inflammatory responses, and matrix degradation, all of which were partially dependent on nuclear factor-κB, extracellular signal-regulated kinase, and c-Jun N-terminal kinase pathways.

• Authors: Dong Yang, Yuanlin Song, Xun Wang, Jiayuan Sun, Yong Ben, Xiaojing An, Lin Tong, Jing Bi, Xiangdong Wang, Chunxue Bai
• Journal: Critical care medicine (Crit Care Med) Vol. 39 Issue 4 Pg. 756-64 (Apr 2011) ISSN: 1530-0293 [Electronic] United States
• PMID: 21200322 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1beta
• Lipopolysaccharides
• NF-kappa B
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• Malondialdehyde
• Hydrogen Peroxide
• Peroxiredoxin VI
• Prdx6 protein, mouse
• Matrix Metalloproteinase 9

Topics

• Acute Lung Injury (etiology, physiopathology)
• Animals
• Hydrogen Peroxide (analysis)
• Interleukin-1beta (analysis)
• Lipopolysaccharides (pharmacology)
• Lung (chemistry, drug effects)
• Macrophages, Peritoneal (chemistry)
• Male
• Malondialdehyde (analysis)
• Matrix Metalloproteinase 9 (analysis)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (analysis)
• Oxidative Stress
• Peroxiredoxin VI (deficiency, physiology)
• Reactive Oxygen Species (analysis)
• Tumor Necrosis Factor-alpha (analysis)